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Volume XV, Number 3, 2011 - Therapeutics Pharmacology and Clinical Toxicology

Review


An overview on nervous conduits and stem cells association

Mihai R., Florescu I.P., Moldovan L., Oancea A., Giuglea C.
Abstract: Nowadays it is unanimously accepted in the specialty scientific medical world that an axon physical guidance is vital for the repair of injured peripheral nerves. Nerve guidance channels represent a diffusion pathway for growth factors secreted by the injured nerves and they also decrease the development of scar tissue. The researches in this domain were axed on the use of natural and synthetic materials for nervous conduits (NC) manufacture. Lately, the studies have been centered on the combination of more materials and bio-molecules in order to develop new composite materials that can stimulate nervous regeneration. Also demonstrated was the importance of neurotrophic factors (neurotrophins, neuronal growth factor, fibroblastic growth factor, etc) and cell adhesion molecules presence. To enhance the performances of the biomaterials used for the manufacture of NC, the effect of Schwann and other cell introduction in these structures was also tested. The biocompatible biomaterial domain is very dynamic, the researches leading to the achievement of new more efficient types. These will improve the prognosis of nerve sections with loss of motor, sensory, or both functions. Peripheral nerve regeneration by mean of efficient NC became a priority for plastic surgeons, neurologists and neurosurgeons. NC achievement in a shape that will ensure patients rapid and precise healing is a challenge for the biomaterial research domain.

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Neurotransmitter receptor and transporter structures

Dahl S. G.
Abstract: Transporter proteins in biological membranes may be divided into channels, which function as selective pores that open in response to a chemical or electrophysiological stimulus, and active carrier proteins using an energy producing process to translocate a substrate against a concentration gradient. Secondary active transporters use the movement of a solute down a concentration gradient to drive the translocation of another substrate across a membrane and against a concentration gradient. The secondary transporters include the neurotransmitter:sodium symporters (NSS family), glucose transporters, and the Escherichia coli lactose permease symporter (Lac Permease). Secondary transporters are very distinct in terms of sequence and function, and transport a wide variety of substances including the monoamine neurotransmitters dopamine, serotonin and noradrenalin. Members of the NSS family are the target of many currently used psychotropic drugs and several substances of abuse. The serotonin transporter (5HTT) and the norepineprine transporter (NET) are the main sites of action of antidepressant drugs, and the dopamine transporter (DAT) is the main site of action of cocaine and other substances of abuse. The rational design of novel drugs interfering with monoamine reuptake is limited by the scarcity of structural information about these transporter proteins. We and others have therefore used molecular modeling techniques to generate 3-dimensional (3D) models of monoamine transporters, based on homology with bacterial membrane transporters and information obtained from site directed mutagenesis studies. 3D modeling of monoamine transporters relies on the availability of experimental 3D structures that may be used as templates. When the crystal structure of a bacterial homologue of the human monoamine neurotransmitter transporters from Aquifex aeolicus (LeuTAa) was reported in 2005, this represented a breakthrough in the structural/functional analysis of monoamine transporters, and provided the possibility of using a homology modeling approach to generate 3D molecular models of NSS family members. These models have demonstrated how transporters may undergo substantial conformational changes during the transport cycle. When performing docking studies on such models, the structural flexibility of transporters should therefore be considered. The conformational flexibility of membrane transporters suggest that different transporter inhibitors may bind to different conformations of the transporter. Computational methods based on accurate molecular transporter models represe nt a useful tool in the discovery of safer and more efficient drugs acting on membrane transporters.

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Original Papers


Non-inferiority study concerning a new analgesic formulation versus an acetylsalicylic acid

Blendea D, Mircioiu I, Sandulovici R, Ghiciuc C, Pricopciuc L, Mircioiu C , Voicu V
Abstract: Headache, one of the most frequent conditions with negative impact on the patient quality of life, represents the reason for over-the-counter self-medication. The aim of this study was to determine the non-inferiority of one tablet of Algopirin, a new analgesic combination (patent RO120818/2006), versus one tablet of Excedrin (Novartis), fixed combination with acetylsalicylic acid, acetaminophen and caffeine for relieving headache. Material and methods. There were included 46 patients diagnosed with headache, which treated two independent headache episodes with 1 tablet of Algopirin, respectively with 1 tablet of Excedrin, in a randomized order. There were recorded: date and time of headache, the time of drug administration, the pain severity using Visual Analogue Scale, before and 30, 60, 120, 180 and 240 min after drug intake, persistence of pain 2 h and 4 h after drug intake. Results. Time to 50% pain relief in mean curves was 60 min for Algopirin and 45 min for Excedrin. Time to 80% pain relief was practically the same for both products (160 min). Comparisons of the two sets of the normalized mean pain intensity curves led to the conclusion that the equivalence hypothesis cannot be rejected. Conclusions. The values of the differences and of the ratio between areas under curve of Algopirin and Excedrin suggest that administration of one tablet of Algopirin is equivalent to one tablet of Excedrin for the treatment of headache. It concerns a clinical point of view, the effect was installed somewhat more rapid in case of Excedrin but the extent was approximately similar. Since doses of active components in Algopirin tablets are half of the doses in Excedrin, Algopirin could be considered as an alternative at least in the case of patients with gastric and hepatic sensibility.

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Investigation of Mechanism Based Inhibition of CYP450 Enzymes

Manar F. Elmadani, Yasser M. Moustafa, Mona F. El-Azab, Olavi Pelkonen
Abstract: The goal of this work was to investigate the mechanism based inhibition of selective model activities for some major xenobiotic-metabolizing enzymes, namely CYP1A1/2, 2A6, 2C8, 2C9, 2C19, 2D6 and 3A4 by certain pesticides. The inhibitory effects were evaluated for different CYP-selective model activities in pooled human hepatic microsomes. At the initial screening of 18 pesticides, chlorpyrifos, fenitrothion, malathion, phenthoate and profenofos displayed the smallest IC50 values towards CYP1A2 and were chosen for the investigation of mechanism based inhibition of CYP1A2, CYP2A6 and CYP2C8 (atrazine in addition for CYP2C8); fenitrothion, malathion, phenthoate, hexaflumuron, glyphosate, chlorfluazuron were chosen for investigating CYP2C9, chlorpyrifos, fenitrothion, phenthoate, abamectin, deltamethrin, lambda-cyhalothrin, fenvalerate for CYP2C19, chlorpyrifos, phenthoate, profenofos, lambda-cyhalothrin, fenvalerate, deltamethrin and carbendazim for CYP2D6 and chlorpyrifos, fenitrothion, phenthoate, lambdacyhalothrin and atrazine for CYP3A4. The results showed that there was no considerable decrease in the IC50 values except for fenitrothion towards CYP2A6, the IC50 values being 23.99 µM for 2-minutes and 4.33 µM for 15-minutes preincubation indicating mechanism based inhibition. Some other pesticides showed decrease in the 15 minutes preincubation IC50 values like chlorpyrifos towards CYP2A6, phenthoate towards CYP2C19 and CYP2C9 and profenofos and carbendazim towards 2D6 however, values were more than 10 µM indicating time dependent inhibition but of weak potency. Otherwise IC50 values for 15 minutes preincubation were either the same as noticed with chlorpyrifos and fenitrothion towards CYP1A2, the IC50 values being 0.56 for both 2 and 15 minutes preincubation (potent inhibition) or even higher than the IC50 values for 2 minutes preincubation indicating reversible inhibition.

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Levocetirizine and Desloratadine have influence on pro-inflammatory cytokines plasmatic level in patients with persistent allergic rhinitis

Bocsan Ioana Corina, Bujor Adriana, Miron N., Negulescu V., Cristea V.
Abstract: Allergic rhinitis is a chronic inflammatory disease which involves different cells and mediators. H1 antihistamines represent first line treatment in patients with allergic rhinitis. We evaluated the effect of H1 antihistamines on symptoms and pro-inflammatory cytokines plasmatic level in patients with persistent allergic rhinitis, after 4 weeks treatment, during continuous exposure to allergens. 79 patients, mean age 30.44±9.90 years, diagnosed with persistent allergic rhinitis were included in the study, divided into 2 groups: 39 patients were under treatment with Desloratadine 5 mg/day and 40 patients received Levocetirizine 5 mg/day for 4 weeks. The patients were evaluated before and after the treatment. We observed the rhinitis symptoms (sneezing, rhinorrhea, nasal congestion, nasal and ocular itching), total symptoms score, type of sensitisation (indoor or outdoor allergens), plasmatic levels of IL-6 and IL-8. H1 antihistamines reduce total symptoms score, especially nasal congestion in patients with allergic rhinitis. IL-6 and IL-8 have no different plasmatic levels in patients with allergic rhinitis compared with the values obtained in healthy volunteers. Levocetirizine reduces the plasmatic level of both IL-6 and IL-8 after 4 weeks of treatment, while Desloratadine has influence only on the IL-6 level.

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The role of atomic absorbtion spectometry in the study of blood lead levels and outlet dialysate lead levels for chronic kidney disease patients

Tudosie M.S., Paun S.C., Macovei R., Ionica M., Ardelean Lumninita, Schiller Oana
Abstract: Some of the naturally occurring chemical elements (like Co, Cr, Cu, Fe, Mg, Mn, Mo, Ni, Se, Sr and V), are essential to life but they also can cause various human problems. Along with these, Lead - as a toxic substance - can affect almost every organ and system in the body. The authors have proposed to study how the levels of this chemical element are modified for the patients with normal renal activity in comparison with the patients with chronic renal failure. In order to determine the chemical elements included in the study, the researchers used an Atomic Absorption Spectrometry in Graphite Furnace (GF-AAS). The levels of Lead have proved to be increased for the patients with chronic renal failure who underwent blood dialysis.

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Antiretroviral treatment in pregnant women: effects on newborns

Cristea Cosmina, Mardarescu Mariana, Anca Ioana Alina, Petre Cristina, Ungurianu Rodica, Drachicenoiu Ruxandra Neagu, Tudor Ana Maria, Vlasceanu Andreia
Abstract: Antiretroviral drugs have been used routinely since 1994 to reduce the risk of mother-to-child transmission of HIV infection, following the AIDS Clinical Trials Group 076 trial, which demonstrated the efficacy of zidovudine in reducing the risk of in utero and intrapartum transmission. Some studies have detected associations between in utero antiretroviral therapy (ARV) exposure and birth defects but evidence is inconclusive. Objective To determine the immunologic status of the children, the number of cardiac abnormalities and other birth defects in a 150 children group of HIV positive mothers and comparing data of birth defects noted in a 73 children group from HIV non-infected mothers. Methods. 150 HIV exposed children were enrolled in the study. Fourteen (9%) were vertically infected with HIV. Birth defects were noted and cardiac anomalies were detected in 36 (24%) children and other congenital anomalies were noted in 28 (18.66%) children. These data were compared with the number of cardiac abnormalities and birth defects in a 73-second group of children born to HIV non-infected mothers. There were no statistical associations between cardiac anomalies in the two groups (p=0.11) but there was statistical association in other defects (p<0, 01). In conclusion, based on current knowledge, the immense benefits of antiretroviral prophylaxis in prevention of mother-to-child transmission outweigh the potential for adverse effects. However, these potential adverse effects require further and longer term monitoring.

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Antimicrobial treatment for infections due to beta-hemolytic group a streptococci

Gavriliu Liana-Catalina, Popescu G. A., Popescu Cristina, Streinu-Cercel A.
Abstract: Group A beta-hemolytic streptococcus is responsible for a variety of infections in humans and is frequently involved in the etiology of bacterial tonsillitis. Its resistance to macrolides is a growing public health problem. Objectives: to analyse the antimicrobial susceptibility rate of group A beta-hemolytic streptococcus and to evaluate its temporal evolution, especially for macrolides. Methods: We analysed the antimicrobial susceptibility tests for group A beta-hemolytic streptococci isolated from patients hospitalized in the National Institute of Infectious Diseases "Prof. Dr. Matei Bals", during July 2009 -June 2010. The temporal evolution of the antimicrobial resistance was studied for the two semesters of the analyzed period, and the evolution of macrolide resistance was further analyzed for shorter periods (four quarters). Results: 172 bacterial strains were analyzed; most of them were isolated from pharyngeal swabs (88.37%). For five classes of antibiotics the susceptibility rate was 100%: penicillin, glycopeptides, linezolid, rifampin, trimethoprim-sulfamethoxazole. Lower rates of susceptibility were found to macrolides (86.47%), clindamycin (85%), fluoroquinolones (98.65%), cyclins (26.16%). The temporal evolution of the susceptibility had no statistical significance for any of the antibiotics that have shown activity under 100% (fluoroquinolones: p = 0.38, macrolides: p = 0.30, clindamycin: p = 0.28). Conclusions: Penicillin remains the antibiotic of choice for the treatment of beta-hemolytic group A streptococcal infections. The current resistance level of beta-hemolytic streptococci to macrolides and clindamycin requires the limitation of their use and, pending the regaining of their efficiency, other therapeutic solutions need to be defined.

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Antimicrobial resistance of Acinetobacter baumannii strains isolated in Matei Bals National Institute of Infectious Diseases

Popescu G.A., Gavriliu Liana-Catalina, Streinu-Cercel A.
Abstract: Acinetobacter baumannii is a gram-negative bacillus with an emerging multiresistance to antibiotics, making more and more difficult the treatment of hospital-acquired infections in which it is involved. Objectives: To analyse the antimicrobial resistance for Acinetobacter baumannii strains, in order to develop the first line treatment alternatives for the syndromes with a frequent involvement of this germ. Methods: The antimicrobial resistance tests of the non-duplicate Acinetobacter baumannii strains were analysed. These strains were isolated from patients hospitalized at the INBI Prof.Dr. Matei Bals between the 1st of July 2008 and June 30, 2010. The evolution of the resistance was studied for the four semesters of the analysed period. Results: 147 strains of Acinetobacter baumannii were analysed. The main specimen which provided the Acinetobacter baumannii isolates was tracheobronchial aspirate (68 strains, 46.25%). More than half of the patients from which the bacteria were isolated had been recently hospitalized in other medical units (55.10%). The proportion of carbapenem resistant strains recorded a slight decrease between the first period (91.42%) and the final period of the study (80.64%), p=0.146. The associations containing sulbactam proved to be efficient in less than 14% of the cases, in each of the studied time periods and the difference in the susceptibility rate was insignificant between the first and the final studied time periods (p=0.78). The level of resistance to amikacin remains high, between 73.07% and 91.3%, and the progressive improvement of susceptibility rates between the analysed periods was insignificant (p=0.10). The efficiency of tobramycin is higher than that of amikacin, but has only reached the level of statistical value in two of the analysed periods. The in vitro resistance of ciprofloxacin was high, rating over 80% in all four intervals. The activity of trimethoprim-sulfamethoxazole was also low and oscillatory, without a significant change between the two time periods (p=0.16). A single strain proved resistance to colistin. Conclusions: Most antibiotics have a less than moderate activity against Acinetobacter baumannii. The only antibiotic that proved a high activity against these strains was colistin; no data were collected for tigecycline.

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Cultures of Helicobacter pylori from string tests and gastric biopsies

Tanasescu Coman, Ilie Madalina, Chifiriuc Mariana Carmen, Popa Marcela
Abstract: Since its discovery in 1982, Helicobacter pylori infection is recognized as a major cause of gastro-intestinal diseases, including chronic gastritis, peptic ulcer disease and gastric malignancy. Its prevalence is connected to socio-economical conditions and most of the individuals are infected during childhood. Regarding Helicobacter pylori treatment, a combination of antibiotics must be given but in certain cases repeated courses of different antibiotics are needed to eradicate H. pylori. Eradicating H. pylori is still a problem because of the rapidly increasing prevalence of multidrug resistant strains worldwide. Aim: In this study we want to emphasize the need for culturing Helicobacter pylori for certain cases and to show the resistance rate to different antibiotics. The samples for culture were obtained either by gastric biopsy taken by upper GI endoscopy or by enterotest - a string test with a small capsule swallowed and removed after 1 hour. For the positive cultures, an antibiotic susceptibility was performed. Some of the empirically used antibiotics showed surprisingly an increased rate of resistance. Materials and methods: We have selected just the patients resistant to the first line therapy (in our case, Clarithromycin 500 mg bid, Amoxicillin, 1g bid and a Pump Proton Inhibitory drug 20 mg bid) dividing them in two groups. For one group gastric biopsy was done and for the other group, enterotest was performed. The samples taken from gastric biopsy and enterotest were put on special media (pylori agar) with microaerophilia for cultivation. Positive culture was obtained after an incubation of three to seven days. To this culture an antibiogram by diffusion method was done. Results: Positive cultures were obtained in 17 patients (out of 20) from gastric biopsy and in 15 patients (out of 20) from enterotest. Increased resistance in Helicobacter pylori strains was observed for Metronidazole and Clarithromycin, commonly used in first line therapy. On the other side, sensitivity was noticed for: Amoxicillin, Ciprofloxacin, Levofloxacin, Furazolidone, Tetracycline. To the patients, a therapy containing an association of two antibiotics from susceptibility testing and a PPI, was given. A good clinical response and a success rate of 93% at one month after finishing the treatment were obtained. The rest of the patients (7%) were retested by rapid urease test or fecal antigen and if they were still positive a second culture was scheduled. Discussions: Many treatment regimens have been proposed for Helicobacter pylori management. The initial approach should be based on the prevalence of drug resistance-especially to Metronidazole and Clarithromycin. Strict adherence to the treatment should be highly recommended to the patient. Reinfection needs to be avoided by respecting basic hygiene rules. Culture seems the best option for cases resistant to classic therapy. Conclusions: Treating Helicobacter pylori can be a challenge when this proves to be resistant to several antibiotics. In these cases, culturing it by gastric biopsy or less invasive, by Enterotest and performing antibiogram afterwards seems an appropriate solution. Cultures have to be examined after at least 72 hours of incubation and negative results can only be certified after seven days of incubation. Metronidazole, a very used antibiotic in first line therapy has a very high resistance and it should be avoided especially if the patient has taken this for other infections.

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Therapeutical Practice


Oxidative stress and antioxidants in brain tumors

Papacocea T., Papacocea R., Badarau A., Ion AD, Buraga I., Gaman L., Papacocea A.
Abstract: The brain has a particular predisposition to oxidative stress which makes it vulnerable to free radicals. They trigger lipid peroxidation of the cellular membranes, oxidation of proteins and DNA leading to changes in chromosome structure, genetic mutation, and/or modulation of cell growth. It was shown that oxygen-derived free radicals play an important role in brain tumor development due to DNA strand braking, appearance of point mutations and aberrant DNA cross-linking. Consequently, a genomic instability is created which contributes to carcinogenesis. In the next steps of carcinogenesis, oxygen free radicals may initiate signal transduction pathways and activate fundamental transcription factors such as NF-kB, Nrf2 or HIF-1. In this context, the contribution of oxidative stress in brain tumors genesis and the role of antioxidants were analysed.

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Medical, legal and ethical implications of toxoplasmosis diagnosis during pregnancy

Bujor-Moraru Mihaela, Ispas Costin Alexandru
Abstract: Toxoplasmosis diagnosis in a pregnant woman brings along a series of medical, legal and also ethical implications regarding the consequent evolution of the pregnancy and the decisions which need to be taken. Starting with the medical implications, represented by the possible fetal affectation, the prenatal diagnosis maneuvers and procedures, the therapy administered throughout the pregnancy, we continue with the legal implications, represented by the necessity and the possibility to test the pregnant woman for toxoplasmosis and by the consequences of an infected mother giving birth to a malformed fetus and we conclude with a series of ethical implications of diagnosing toxoplasmosis during pregnancy.

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In vitro evaluation of effectiveness in reducing bacterial plaque of antimicrobial substances in patients treated with orthodontic appliances

Vizitiu Th.-C., Ionescu Ecaterina
Abstract: Orthodontic devices create, in the absence of adequate prophylactic measures, favorable conditions for the development of dental plaque. The aim of this study was to evaluate the effectiveness in reducing the bacterial load of the disinfectants from commercially available mouthwashes that are currently used by orthodontic patients. An experimental model has been developed which was used to investigate the action of antimicrobials contained in three commercial mouthwashes on microorganisms (total bacteria culture and Streptococcus mutans culture) isolated from dental plaque and cultured in vitro on the surface of orthodontic devices and growth media. Mouthwashes used in the experiment were three commercial products containing: 1) herbal extracts (essential oils): eucalyptol - 0.09%, menthol - 0.04%, thymol - 0.06%, methyl salicylate - 0.06%; 2) chlorhexidine gluconate - 0.2%; 3) sodium fluoride - 225 ppm. The experiments used in this study proved that chlorhexidine, whose application has drastically reduced the CFU/ml number for both total bacteria and S. mutans, has the biggest effectiveness of the tested antimicrobials. The next place, for the total bacterial flora, was the mouthwash containing extracts of plants and the lowest antimicrobial activity was recorded for the mouthwash containing sodium fluoride. For the Streptococcus mutans culture, sodium fluoride ranked second in effectiveness after chlorhexidine, and the mouthwash with herbal disinfectants had the lowest activity. Decrease of bacterial load in the presence of the three mouthwashes underlines the importance of rigorous preventive measures during orthodontic treatment, reducing the risks of dental demineralization and periodontal inflammation.

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Case Report


Nail-Patella Syndrome

Stoica Cristina, Chiriac-Babei Gh., Vasilescu Mariana, Matei Roxana, Lungu A., Joiteanu Monica
Abstract: The authors present the case of a sixteen year-old boy with significant family history (father with chronic kidney disease who received a living related donor kidney transplant), admitted in our department for hematuria, skeletal abnormalities and antecubital pterygia. The renal function and systemic involvements were evaluated and imagistic tests were performed. A surveillance and therapeutic plan were performed.

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A prosthetic solution for restricted posterior vertical space in conventional complete denture treatment.

Radu Ioana, Andrei Oana Cella
Abstract: The case described in this paper presents the benefit of metal castings over the tuberosities and retromolar pads in complete dentures. The patient is 46 years old, female, and she has been wearing the same complete dentures for 4 years. The old complete dentures showed an overvalued occlusal vertical dimension and the patient complained of headaches, clicks, discomfort and important diet changes. The replacement of the old dentures with the new ones made in a correct vertical dimension increased the comfort and made the pain disappear. The overestimated occlusal vertical dimension was corrected by the new complete dentures made with metal castings over the tuberosities and pads.

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